This invention relates to novel 4-oxo-butenoic acid derivatives and to the use of these compounds and related compounds with novel biological activity in humans as therapeutic means for the prevention and treatment of the human breast cancer and claims the benefit of priority of U.S. Provisional Application Serial No. 60/286,823 filed Jun. 8, 2001.
Cancer is a global killer of humans with breast cancer among the leaders of killing humans yearly. Breast cancer is the primary killer of women. One in eight American women will develop breast cancer in her lifetime. In 2001, an estimated 192,700 women in the U.S. will be diagnosed with invasive breast cancer and 42,600 with in situ (tumors contained in the milk ducts). An estimated 40,000 will die from the disease.
An estimated 3 million women in the U.S. today are living with breast cancer of which 2 million have been diagnosed with the disease and 1 million have the disease but do not yet know it.
The incidence of breast cancer in the U.S. has more than doubled in the past 30 years. In 1964, the lifetime risk was 1 in 20. Today it""s 1 in 8. Breast cancer is the most commonly diagnosed cancer in women in both America and worldwide. Breast cancer rates are the highest in industrialized countries. It is estimated that 1.2 million new diagnoses and 500,000 deaths from breast cancer will occur worldwide this year. Further, it appears that breast cancer is the leading cause of death for American women of ages 25 to 55 years.
No vaccine or other universally successful method for the prevention or treatment of breast cancer is currently available. Management of the disease currently relies on a combination of early diagnosis (through routine breast screening procedures) and aggressive treatment, which may include one or more of a variety of treatments such as surgery, radiotherapy, chemotherapy and hormone therapy. The course of treatment for a particular breast cancer is often selected based on a variety of prognostic parameters, including an analysis of specific tumor markers. {Porter-Jordan and Lippman, Breast Cancer 8:73-100 (1994)}. However, the use of established markers often leads to a result that is difficult to interpret, and the high mortality observed in breast cancer patients indicates that improvements are needed in the treatment, diagnosis and prevention of the disease.
Accordingly, there is a need for improved methods for chemotherapy for breast cancer. The present invention fulfills this need and further provides other related advantages.
The U.S. patent literature has many disclosures of oxo-butenoic (crotonic) acid derivatives:
Pamukci (U.S. Pat. No. 6,232,312) describes crotonic acid derivatives (column 22, lines 43-58) for the treatment of colonic polyps;
Jones et al (U.S. Pat. No. 6,121,450) discloses crotonic acid derivatives (column 8, tine 34; column 78, line 24 and at example 34 as steroid modifiers in treating breast cancer (column 1, lines 55-58);
Kalden, et al (U.S. Pat. No. 5,334,612) discloses compounds said to be useful for treating AIDS including derivatives of carboxylic acid (column 9, line 31) and pyrrolidine (column 7, line 24);
Brown (U.S. Pat. No. 6,066,670) describes an anti-viral admixture containing crotonic acid for treating tumors (see Abstract);
Horwell, et al (U.S. Pat. No. 5,580,896) discloses many 4-oxo-2-butenoic acid derivatives (column 13, lines 21-59; also in columns 15+, examples 25,26,32,34,40,43-46,77-79,97,99,103,106,), which are useful for inhibiting colorectal cancer, i.e., colon cancer (Abstract); and,
Giordani, et al (U.S. Pat. No. 5,580,890) discloses 4-oxo-2-butenoic acid derivatives said to be useful for treatment of AIDS (column 1, line 8 and column 2, line 61; and,
Yonemeto, et al (U.S. Pat. No. 6,083,985) recites a number of anti-tumor or anti-AIDS agents that include butenoic acid derivatives.
The U.S. patent literature has many disclosures of butanoic acid derivatives including:
Nicolai, et al (U.S. Pat. No. 6,180,651) discloses many anti-inflammatory and analgesic compounds, including adenocarcinoma (column 1, line 55), which includes heterocyclic alcohol-esters (column 11, lines 1-16) and butanoic acid derivatives (many Examples including 47 through 162);
Girard, et al (U.S. Pat. No. 5,308,852) discloses many compounds including butanoic acid derivatives (see Methods B and C of schemes II and III) which compounds which are said to inhibit tumor metastasis (column 7, line 56 and column 8, line 4); and,
Frechette (U.S. Pat. No. 5,696,117), Frechette (U.S. Pat. No. 5,854,242) and Frechette (U.S. Pat. No. 5,707,990) describe 148 benzoxazine and pyrido-oxazine heterocyclics as anti-bacterial compounds.
It appears from the foregoing that the derivatives of 4-oxo-butanoic acid of interest are not disclosed and thus there is no report of their activity against human breast cancer.
Consequently, there is a need for an anti-cancer drug for humans that mitigates the above mentioned disadvantages of current drug therapy and effectiveness against human breast cancer.
The first objective of the present invention is to provide a drug effective for treatment of human breast cancer.
Another object of this invention is to provide novel 4-oxo-butenoic acid derivatives.
A further object of this invention is to provide 4-oxo-butenoic acid derivatives with novel activity against human breast cancer.
A preferred embodiment of the invention encompasses a class of compounds having the property of anti-tumor activity against human breast cancer comprising the novel structures of 4-oxo-butenoic derivatives and more specifically those derivatives: 2-(Nxe2x80x2-Fluoren-9-ylidene-hydrazino)-5,5-dimethyl-4-oxo-hex-2-enoic acid methyl ester (OF-06), 1-(2,4-Dimethyl-phenyl)-2,4-dihydroxy-3-(4-methyl-benzoyl)-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1F-07), 4-(4-Methoxy-phenyl)-2,4-dioxo-3-(phenyl-hydrazono)-butyric acid (3F-10), 4-(4-Chloro-phenyl)-2,4-dioxo-3-(phenyl-hydrazono)-butyric acid ethyl ester (3F-11), 2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxy-phenyl)-but-2-enoic acid (3F-15), and 4,4-Dihydroxy-5-(4-methyl-benzoyl)-2-phenyl-2,4-dihydro-pyrazol-3-one (3F-16) as well as novel derivatives of these compounds (see Table 2).
The use of the following compounds for humans as therapeutic means for the eradication of human breast cancer further encompasses the following: 4-(4-Ethoxy-phenyl)-2-(Nxe2x80x2-fluoren-9-ylidene-hydrazino)-2-hydroxy-4-oxo-butyric acid methyl ester (OF-13); 2-{Nxe2x80x2-[1-(4-Chloro-phenyl)-ethylidene]-hydrazino}-4-oxo-4-phenyl-but-2-enoic acid methyl ester (OF-20); 2-(Nxe2x80x2-Fluoren-9-ylidene-hydrazino)-4-oxo-4-phenyl-but-2-enoic acid methyl ester (1F-04); and 4-Chloro-4-(4-ethoxy-phenyl)-2-(fluoren-9-ylidene-hydrazono)-but-3-enoic acid methyl ester (3F-19).